This BRP proposal from the University of Pennnsylvania is a partnership of interdisciplinary scientists in bioengineering and medical research focused on the biomechanics of cardiovascular cells, membranes, and tissues in the context of site-specific therapy and tissue engineering. Complementary design-driven and hypothesis-driven approaches to vascular cell physiology and pathology are proposed. The center for the program is the Institute for Medicine and Engineering located centrally on the Penn campus. There is a subcontract to Childrens Hospital of Philadelphia (CHOP) and a collaborative partnership with N.I.S.T. The Partnership is composed of two interactive components: (i) fundamental cell and molecular investigations of cardiovascular mechanotransduction. and (ii) preclinical studies of engineered arteries, heart valve calcification, and microcoil treatment of intracranial aneurysms. The basic studies focus on the continuum of force-membrane-cytoskeleton-adhesion and extracellular matrix. The experimental approaches include geometric constraints, spatial analyses, protein conformational changes, deformation properties, and mass transport characteristics that regulate vascular cell structure, gene expression, function, and maladaptation to hemodynamic forces that may lead to pathological change. Also proposed are the development of new materials to regulate cell adhesion (and hence phenotype), and for the delivery of therapeutics in situ. Parallel, complementary preclinical studies focus on tissue engineered arteries ex vivo, heart valve pathology (both ex vivo and in vivo), and the delivery of therapeutic factors to correct intracranial aneurysms in vivo. Specific first year objectives include quantitative spatial analyses of cell deformation, localization of mechanically-induced protein conformational changes, analyses of protein phosphorylation, and the first alterations of cell mechanics through manipulations of substrate chemistry. The preclinical short-term objectives are sustained retention of structure and function of arteries maintained ex vivo and their reintroduction in vivo, the elucidation of heart valve gene expression, and both in vitro and in vivo evaluation of the release of potential therapeutic agents from coated platinum microcoils. The proposal addresses the objectives of the BRP program by integrating physical, chemical, and engineering sciences into fundamental and preclinical studies of vascular mechanotransduction, and by developing innovative materials and devices for both basic research and clinical therapy.